Lymphangioleiomyomatosis Diagnosis and Management: High-Resolution Chest Computed Tomography, Transbronchial Lung Biopsy, and Pleural Disease Management. An Official American Thoracic Society/Japanese Respiratory Society Clinical Practice Guideline.

BACKGROUND: Recommendations regarding key aspects related to the diagnosis and pharmacological treatment of lymphangioleiomyomatosis (LAM) were recently published. We now provide additional recommendations regarding four specific questions related to the diagnosis of LAM and management of pneumothoraces in patients with LAM. METHODS: Systematic reviews were performed and then discussed by a multidisciplinary panel. For each intervention, the panel considered its confidence in the estimated effects, the balance of desirable (i.e., benefits) and undesirable (i.e., harms and burdens) consequences, patient values and preferences, cost, and feasibility. Evidence-based recommendations were then formulated, written, and graded using the GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) approach. RESULTS: For women who have cystic changes on high-resolution computed tomography of the chest characteristic of LAM, but who have no additional confirmatory features of LAM (i.e., clinical, radiologic, or serologic), the guideline panel made conditional recommendations against making a clinical diagnosis of LAM on the basis of the high-resolution computed tomography findings alone and for considering transbronchial lung biopsy as a diagnostic tool. The guideline panel also made conditional recommendations for offering pleurodesis after an initial pneumothorax rather than postponing the procedure until the first recurrence and against pleurodesis being used as a reason to exclude patients from lung transplantation. CONCLUSIONS: Evidence-based recommendations for the diagnosis and treatment of patients with LAM are provided. Frequent reassessment and updating will be needed.

Heme Oxygenase-1 Deficiency Diminishes Methicillin-Resistant Staphylococcus aureus Clearance Due to Reduced TLR9 Expression in Pleural Mesothelial Cells.

Methicillin Resistant Staphylococcus aureus (MRSA) cause pneumonia and empyema thoraces. TLR9 activation provides protection against bacterial infections and Heme oxygenase-1 (HO-1) is known to enhance host innate immunity against bacterial infections. However, it is still unclear whether HO-1 regulates TLR-9 expression in the pleura and modulates the host innate defenses during MRSA empyema. In order to determine if HO-1 regulates host innate immune functions via modulating TLR expression, in MRSA empyema, HO-1+/+ and HO-1-/- mouse pleural mesothelial cells (PMCs) were infected with MRSA (1:10, MOI) in the presence or absence of Cobalt Protoporphyrin (CoPP) and Zinc Protoporphyrin (ZnPP) or CORM-2 (a Carbon monoxide donor) and the expression of mTLR9 and mBD14 was assessed by RT-PCR. In vivo, HO-1+/+ and HO-1-/- mice were inoculated with MRSA (5x106 CFU) intra-pleurally and host bacterial load was measured by CFU, and TLR9 expression in the pleura was determined by histochemical-immunostaining. We noticed MRSA inducing differential expression of TLR9 in HO-1+/+ and HO-1 -/- PMCs. In MRSA infected HO-1+/+ PMCs, TLR1, TLR4, and TLR9 expression was several fold higher than MRSA infected HO-1-/- PMCs. Particularly TLR9 expression was very low in MRSA infected HO-1-/- PMCs both in vivo and in vitro. Bacterial clearance was significantly higher in HO-1+/+ PMCs than compared to HO-1-/- PMCs in vitro, and blocking TLR9 activation diminished MRSA clearance significantly. In addition, HO-1-/- mice were unable to clear the MRSA bacterial load in vivo. MRSA induced TLR9 and mBD14 expression was significantly high in HO-1+/+ PMCs and it was dependent on HO-1 activity. Our findings suggest that HO-1 by modulating TLR9 expression in PMCs promotes pleural innate immunity in MRSA empyema.

Official American Thoracic Society/Japanese Respiratory Society Clinical Practice Guidelines: Lymphangioleiomyomatosis Diagnosis and Management.

BACKGROUND: Lymphangioleiomyomatosis (LAM) is a rare cystic lung disease that primarily affects women. The purpose of these guidelines is to provide recommendations for the diagnosis and treatment of LAM. METHODS: Systematic reviews were performed to summarize evidence pertinent to our questions. The evidence was summarized and discussed by a multidisciplinary panel. Evidence-based recommendations were then formulated, written, and graded using the Grading of Recommendations, Assessment, Development, and Evaluation approach. RESULTS: After considering the panel's confidence in the estimated effects, the balance of desirable (i.e., benefits) and undesirable (i.e., harms and burdens) consequences of treatment, patient values and preferences, cost, and feasibility, recommendations were formulated for or against specific interventions. These included recommendations for sirolimus treatment and vascular endothelial growth factor D testing and recommendations against doxycycline and hormonal therapy. CONCLUSIONS: Evidence-based recommendations for the diagnosis and treatment of patients with LAM are provided. Frequent reassessment and updating will be needed.

Pleural Fluid Analysis in Chronic Hemothorax: A Mimicker of Infection.

OBJECTIVES: Timing to video-assisted thoracoscopic surgery (VATS) in hemothorax is based on preventing acute and long-term complications of retained blood products in the pleural space, including pleural space infection. We propose that the persistence of blood in the pleural space induces a proinflammatory state, independent of active infection. METHODS: We identified six patients with a hemothorax by clinical history, radiographic imaging, and pleural fluid analysis from a database of 1133 patients undergoing thoracentesis from 2002 to 2010 at the Medical University of South Carolina. RESULTS: In four of the six patients identified, the time from injury to thoracentesis was one, four, four, and five days, respectively. The fluid pH range was 7.32-7.41. The lactate dehydrogenase (LDH) range was 210-884 IU/L (mean 547 IU/L), and the absolute neutrophil count (ANC) range was 1196-3631 cells/µL. In two patients, the time from injury to thoracentesis was 7 and 60 days. In these two patients, the pH was 7.18 and 6.91, LDH was 1679 and 961 IU/L, and the ANC was 8134 and 5943 cells/µL. Microbiology and pathology were negative in all patients. CONCLUSIONS: The persistence of blood outside the vascular compartment, and within the pleural space, biochemically mirrors infection. We will explore the multiple mechanisms that account for development of pleural fluid acidosis, inflammation, and neutrophil recruitment.

Validation of test performance characteristics and minimal clinically important difference of the 6-minute walk test in patients with idiopathic pulmonary fibrosis.

BACKGROUND: The 6-minute walk test distance (6MWD) has been shown to be a valid and responsive outcome measure in patients with idiopathic pulmonary fibrosis (IPF). The analyses were based, however, on a single phase 3 trial and require validation in an independent cohort. OBJECTIVE: To confirm the performance characteristics and estimates of minimal clinically important difference (MCID) of 6MWD in an independent cohort of patients with IPF. METHODS: Patients randomized to placebo in the phase 3 CAPACITY trials who had a baseline 6MWD measurement were included in these analyses. The 6MWD and other functional parameters (lung function, dyspnea, and health-related quality of life) were measured at baseline and 24-week intervals. Validity and responsiveness were examined using Spearman correlation coefficients. The MCID was estimated using distribution- and anchor-based methods. RESULTS: The analysis comprised 338 patients. Baseline 6MWD was significantly correlated with lung function measures, patient-reported outcomes, and quality-of-life measures (validity). Compared with baseline 6MWD, change in 6MWD (responsiveness) showed stronger correlations with change in lung function parameters and quality-of-life measures. Dyspnea measured by the University of California San Diego Shortness of Breath Questionnaire showed the strongest correlations with 6MWD (baseline: coefficient -0.35; 48-week change: coefficient -0.37; both p < 0.001). The distribution-based analyses of MCID using standard error of measurement yielded an MCID of 37 m, and distribution-based analyses by effect size resulted in 29.2 m. The MCID by anchor-based analysis using criterion referencing (health events of hospitalization or death) was 21.7 m. CONCLUSIONS: The 6MWD is a valid and responsive clinical endpoint, which provides objective and clinically meaningful information regarding functional status and near-term prognosis. These results confirm previous findings in an independent cohort of patients with IPF.

Sensitivity Analyses of the Change in FVC in a Phase 3 Trial of Pirfenidone for Idiopathic Pulmonary Fibrosis.

BACKGROUND: FVC outcomes in clinical trials on idiopathic pulmonary fibrosis (IPF) can be substantially influenced by the analytic methodology and the handling of missing data. We conducted a series of sensitivity analyses to assess the robustness of the statistical finding and the stability of the estimate of the magnitude of treatment effect on the primary end point of FVC change in a phase 3 trial evaluating pirfenidone in adults with IPF. METHODS: Source data included all 555 study participants randomized to treatment with pirfenidone or placebo in the Assessment of Pirfenidone to Confirm Efficacy and Safety in Idiopathic Pulmonary Fibrosis (ASCEND) study. Sensitivity analyses were conducted to assess whether alternative statistical tests and methods for handling missing data influenced the observed magnitude of treatment effect on the primary end point of change from baseline to week 52 in FVC. RESULTS: The distribution of FVC change at week 52 was systematically different between the two treatment groups and favored pirfenidone in each analysis. The method used to impute missing data due to death had a marked effect on the magnitude of change in FVC in both treatment groups; however, the magnitude of treatment benefit was generally consistent on a relative basis, with an approximate 50% reduction in FVC decline observed in the pirfenidone group in each analysis. CONCLUSIONS: Our results confirm the robustness of the statistical finding on the primary end point of change in FVC in the ASCEND trial and corroborate the estimated magnitude of the pirfenidone treatment effect in patients with IPF. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT01366209; URL: www.clinicaltrials.gov.

Analysis of lung function and survival in RECAP: An open-label extension study of pirfenidone in patients with idiopathic pulmonary fibrosis.

BACKGROUND: RECAP is an open-label extension study evaluating pirfenidone in patients with idiopathic pulmonary fibrosis (IPF) who completed the Phase 3 CAPACITY program. OBJECTIVE: We examined the effect of pirfenidone on lung function and survival in patients who were previously randomised to the placebo group in one of the two CAPACITY studies and received pirfenidone for the first time in RECAP. METHODS: Eligible patients received oral pirfenidone 2403 mg/day. Forced vital capacity (FVC) was measured at baseline and at weeks 12, 36, and 60. To facilitate comparison with CAPACITY outcomes, analyses were based on patients newly treated with pirfenidone in RECAP who had baseline FVC and carbon monoxide diffusing capacity (DLCO) values that met CAPACITY entry criteria. RESULTS: A total of 178 patients were included in the analysis. Among these, 16.3% experienced an FVC decline ≥10% at week 60, compared with 16.8% and 24.8%, respectively, in the CAPACITY pirfenidone (n=345) and placebo (n=347) groups. The mean change from baseline to week 60 in %FVC was -5.9%, compared with -7.0% and -9.4% in the CAPACITY pirfenidone and placebo groups. Overall survival was similar to that of pirfenidone treated patients in CAPACITY. Treatment was safe and generally well tolerated; the type and frequency of adverse events were consistent with previous clinical experience. CONCLUSION: FVC and survival outcomes in IPF patients newly treated with pirfenidone in RECAP were similar to those in the CAPACITY pirfenidone group. These data provide further evidence to support the use of pirfenidone in patients with IPF.

Characteristics of patients with yellow nail syndrome and pleural effusion.

Yellow nail syndrome (YNS) can be associated with a pleural effusion (PE) but the characteristics of these patients are not well defined. We performed a systematic review across four electronic databases for studies reporting clinical findings, PE characteristics, and most effective treatment of YNS. Case descriptions and retrospective studies were included, unrestricted by year of publication. We reviewed 112 studies (150 patients), spanning a period of nearly 50 years. The male/female ratio was 1.2/1. The median age was 60 years (range: 0-88). Seventy-eight percent were between 41-80 years old. All cases had lymphoedema and 85.6% had yellow nails. PEs were bilateral in 68.3%. The appearance of the fluid was serous in 75.3%, milky in 22.3% and purulent in 3.5%. The PE was an exudate in 94.7% with lymphocytic predominance in 96% with a low count of nucleated cells. In 61 of 66 (92.4%) of patients, pleural fluid protein values were >3 g/dL, and typically higher than pleural fluid LDH. Pleurodesis and decortication/pleurectomy were effective in 81.8% and 88.9% of cases, respectively, in the treatment of symptomatic PEs. The development of YNS and PE occurs between the fifth to eighth decade of life and is associated with lymphoedema. The PE is usually bilateral and behaves as a lymphocyte-predominant exudate. The most effective treatments appear to be pleurodesis and decortication/pleurectomy.

A phase 3 trial of pirfenidone in patients with idiopathic pulmonary fibrosis.

BACKGROUND: In two of three phase 3 trials, pirfenidone, an oral antifibrotic therapy, reduced disease progression, as measured by the decline in forced vital capacity (FVC) or vital capacity, in patients with idiopathic pulmonary fibrosis; in the third trial, this end point was not achieved. We sought to confirm the beneficial effect of pirfenidone on disease progression in such patients. METHODS: In this phase 3 study, we randomly assigned 555 patients with idiopathic pulmonary fibrosis to receive either oral pirfenidone (2403 mg per day) or placebo for 52 weeks. The primary end point was the change in FVC or death at week 52. Secondary end points were the 6-minute walk distance, progression-free survival, dyspnea, and death from any cause or from idiopathic pulmonary fibrosis. RESULTS: In the pirfenidone group, as compared with the placebo group, there was a relative reduction of 47.9% in the proportion of patients who had an absolute decline of 10 percentage points or more in the percentage of the predicted FVC or who died; there was also a relative increase of 132.5% in the proportion of patients with no decline in FVC (P<0.001). Pirfenidone reduced the decline in the 6-minute walk distance (P=0.04) and improved progression-free survival (P<0.001). There was no significant between-group difference in dyspnea scores (P=0.16) or in rates of death from any cause (P=0.10) or from idiopathic pulmonary fibrosis (P=0.23). However, in a prespecified pooled analysis incorporating results from two previous phase 3 trials, the between-group difference favoring pirfenidone was significant for death from any cause (P=0.01) and from idiopathic pulmonary fibrosis (P=0.006). Gastrointestinal and skin-related adverse events were more common in the pirfenidone group than in the placebo group but rarely led to treatment discontinuation. CONCLUSIONS: Pirfenidone, as compared with placebo, reduced disease progression, as reflected by lung function, exercise tolerance, and progression-free survival, in patients with idiopathic pulmonary fibrosis. Treatment was associated with an acceptable side-effect profile and fewer deaths. (Funded by InterMune; ASCEND ClinicalTrials.gov number, NCT01366209.).

Comprehensive assessment of the long-term safety of pirfenidone in patients with idiopathic pulmonary fibrosis.

BACKGROUND AND OBJECTIVE: Pirfenidone is an oral antifibrotic agent that is approved in several countries for the treatment of idiopathic pulmonary fibrosis (IPF). We performed a comprehensive analysis of safety across four clinical trials evaluating pirfenidone in patients with IPF. METHODS: All patients receiving pirfenidone 2403 mg/day in the Phase 3 CAPACITY studies (Studies 004 and 006) and all patients receiving at least one dose of pirfenidone in one of two ongoing open-label studies in patients with IPF (Studies 002 and 012) were selected for inclusion. Safety outcomes were evaluated from baseline until 28 days after the last dose of study drug. RESULTS: A total of 789 patients were included in the analysis. The median duration of exposure to pirfenidone was 2.6 years (range, 1 week-7.7 years), and the cumulative total exposure was 2059 person exposure years (PEY). Gastrointestinal and skin-related events were the most commonly reported adverse events; these were almost always mild to moderate in severity, and rarely led to treatment discontinuation. Elevations (>3× upper limit of normal) in alanine aminotransferase (ALT) or aspartate aminotransferase (AST) occurred in 21/789 (2.7%) patients; the adjusted incidence of AST/ALT elevations was 1.7 per 100 PEY. CONCLUSIONS: This comprehensive analysis of safety in a large cohort of IPF patients receiving pirfenidone for a total of 2059 PEY demonstrates that long-term treatment with pirfenidone is safe and generally well tolerated.

All-cause mortality rate in patients with idiopathic pulmonary fibrosis. Implications for the design and execution of clinical trials.

RATIONALE: FVC has emerged as a standard primary endpoint in clinical trials evaluating novel therapies for patients with idiopathic pulmonary fibrosis (IPF). However, it has recently been proposed that all-cause mortality or a composite comprised of all-cause mortality and all-cause nonelective hospitalization be adopted as the standard primary endpoint for IPF clinical trials. OBJECTIVES: To conduct a comprehensive evaluation of mortality in three phase 3 clinical trials and evaluate the feasibility of mortality trials in patients with IPF. METHODS: The study population included 622 patients randomized to placebo in the CAPACITY studies evaluating pirfenidone (n = 347) or the INSPIRE study evaluating interferon-γ1b (n = 275). The Kaplan-Meier estimate of 2-year survival was fit to the exponential distribution and used to calculate sample size requirements for a mortality study with 90% power to detect a 25% reduction in all-cause mortality with a two-sided α of 0.05. Modeling analyses were used to assess the effects of selected variables on sample size and study design. MEASUREMENTS AND MAIN RESULTS: A total of 73 deaths occurred during the period of observation (mean duration of follow-up, 80.1 wk). The all-cause mortality rate was 6.6% at 1 year and 13.7% at 2 years. Based on the observed 2-year mortality rate, a total of 508 events would be required to detect a significant treatment benefit in a two-arm trial with 90% power to detect a 25% reduction in all-cause mortality. The estimated sample size for a trial enrolled over 3 years with a maximum follow-up period of 5 years is 2,582 patients. CONCLUSIONS: The all-cause mortality rate is relatively low in patients with IPF with mild to moderate impairment in lung function. Accordingly, the necessary size, duration, and cost of all-cause mortality trials in this population are substantial and likely prohibitive.

Improving the predictive accuracy of identifying exudative effusions.

BACKGROUND: Application of Light's criteria results in misclassification of some transudative effusions as exudative, particularly because of congestive heart failure (CHF). We sought to determine if the serum to pleural fluid albumin (SF-A) and serum to pleural fluid protein (SF-P) gradients increased the predictive accuracy to correctly identify exudative effusions. METHODS: We retrospectively analyzed 1,153 consecutive patients who underwent a diagnostic thoracentesis at the Medical University South Carolina. Univariable logistic regression analyses were used to determine the statistical significance of pleural fluid tests that correctly identified exudative effusions. Tests with significant diagnostic accuracy were combined in multivariable logistic regression models, with calculation of areas under the curve (AUCs) to determine their predictive accuracy. The predictive capability of the best model was compared with Light's criteria and other test combinations. RESULTS: Pleural fluid lactate dehydrogenase (LDH), SF-A gradient, and SF-P gradient had a significant effect on the probability of identifying exudative pleural effusions. When combined together in a multivariable logistic regression, LDH (OR, 14.09 [95% CI, 2.25-85.50]), SF-A gradient (OR, 7.16 [95% CI, 1.24-41.43]), and SF-P gradient (OR, 6.83 [95% CI, 1.56-27.88]) had an AUC of 0.92 (95% CI, 0.85-0.98). CONCLUSIONS: Application of Light's criteria, not uncommonly, misclassifies CHF transudative effusions as exudates. In cases where no cause for an exudative effusion can be identified or CHF is suspected, the sequential application of the fluid LDH, followed by the SF-P and then the SF-A gradients, may assist in reclassifying pleural effusions as transudates.

6-Minute walk distance is an independent predictor of mortality in patients with idiopathic pulmonary fibrosis.

6-min walk distance (6MWD) has recently been shown to be associated with the risk of mortality in patients with idiopathic pulmonary fibrosis (IPF); however, the independent contribution of 6MWD to the prediction of mortality risk has not been evaluated in a large, well-defined population of patients with IPF. A Cox proportional hazards model was used to characterise the relationship between risk factors of interest and all-cause mortality in IPF patients who completed a week 24 study visit in a clinical trial evaluating interferon γ-1b (n=748). Risk factors of interest included the independent predictors of mortality in the previously published clinical prediction model together with 6MWD and 24-week change in 6MWD. Baseline 6MWD <250 m was associated with a two-fold increase in the risk of mortality (hazard ratio 2.12, 95% CI 1.15-3.92) and a 24-week decline in 6MWD >50 m was associated with a nearly three-fold increase in mortality risk (hazard ratio 2.73; 95% CI 1.60-4.66). Inclusion of 6MWD data improved model discrimination compared with the original model (C-statistic 0.80 (95% CI 0.76-0.85) versus 0.75 (0.71-0.79)). Both 6MWD and change in 6MWD are independent predictors of mortality in patients with IPF. The addition of 6MWD to the clinical prediction model improves model discrimination compared with the original model.

Effects of coexisting pneumonia and end-stage renal disease on pleural fluid analysis in patients with hydrostatic pleural effusion.

BACKGROUND: In individual patients, especially those who are hospitalized, several conditions often coexist that may be responsible for the development of a pleural effusion and may affect the pleural fluid analysis (PFA). The objective of this study was to investigate the effects of end-stage renal disease and pneumonia on PFA in patients with hydrostatic pleural effusion. METHODS: In a retrospective analysis of 1,064 consecutive patients who underwent thoracentesis at a university hospital, cell counts and pleural fluid protein, lactate dehydrogenase, pH, and glucose levels were examined in those (n = 300) with clinical evidence of hydrostatic pleural effusion. RESULTS: The 300 patients (28.1%) with pleural effusions had congestive heart failure (CHF), circulatory overload (CO), or both. Expert consensus was achieved in 66 (22%) for CHF as the sole diagnosis (SCHF), 30 (10%) for CHF and coexisting pneumonia (PCHF), and 26 (8.7%) for end-stage renal disease (ESRD) with coexisting CO or CHF. The remaining 178 patients were excluded because of complicating conditions. There were minor, but statistically significant differences in pleural fluid/serum protein ratios in patients with ESRD with coexisting CO or CHF compared with SCHF. Compared with SCHF, there were statistically significant tendencies for higher protein and lactate dehydrogenase concentrations and lower pH levels in those with PCHF. The total nucleated cell count and the absolute neutrophil count were significantly higher in PCHF. CONCLUSIONS: ESRD in patients with hydrostatic pleural effusions has a minimal effect on the PFA. Coexisting pneumonia most often results in an exudative effusion in patients with CHF.

Parasitic diseases of the pleura.

Parasitic infections are prevalent in certain parts of the world and may cause pleural involvement, which often goes unrecognized. Common parasites involving the pleura include Entamoeba histolytica, Echinococcus granulosus and Paragonimus westermani. Amebiasis can cause empyema with "anchovy sauce" pus, reactive pleural effusions and bronchopleural fistula with hydropneumothorax. Echinococcosis may result in pleural thickening, pneumothorax, secondary pleural hydatidosis and pleural effusions. Paragonimiasis may cause chylous and cholesterol pleural effusions, pleural thickening and pneumothorax. Less commonly, pulmonary eosinophilia, or Loeffler's syndrome, caused by Ascaris lumbricoides, Ancylostoma duodenale and Necator americanus and tropical pulmonary eosinophilia caused by Wuchereria bancrofti and Brugia malayi may involve the pleura. This article provides a comprehensive review of parasitic infections involving the pleura. A high index of suspicion in the appropriate clinical setting is required to facilitate prompt diagnosis and treatment of these diseases.

Unusual bacterial infections and the pleura.

Rickettsiosis, Q fever, tularemia, and anthrax are all bacterial diseases that can affect the pleura. Rocky Mountain Spotted Fever (RMSF) and Mediterranean Spotted Fever (MSF) are caused by Rickettsia rickettsii and Rickettsia conorii, respectively. Pleural fluid from a patient with MSF had a neutrophil-predominant exudate. Coxiellaburnetii is the causative agent of Q fever. Of the two cases described in the literature, one was an exudate with a marked eosinophilia while the other case was a transudate due to a constrictive pericarditis. Francisella tularensis is the causative agent of tularemia. Pleural fluid from three tularemia patients showed a lymphocyte predominant exudate. Bacillusanthracis is the causative agent of anthrax. Cases of inhalational anthrax from a recent bioterrorist attack evidenced the presence of a serosanguineous exudative pleural effusion. These four bacterial microorganisms should be suspected in patients presenting with a clinical history, exposure to known risk factors and an unexplained pleural effusion.

Getting the most from pleural fluid analysis.

Virtually, every pulmonary disease and most non-pulmonary diseases may be associated with a pleural effusion. The presence of a pleural effusion allows the clinician to 'diagnose' or narrow the differential diagnosis and aetiology of the fluid collection. However, pleural fluid analysis (PFA) in isolation rarely provides a definitive diagnosis. This review discusses the rationale for evaluating patients with a pleural effusion. If the clinician obtains a detailed history, performs a comprehensive physical examination, reviews pertinent blood tests, and evaluates the chest imaging findings prior to thoracentesis, there should be a high likelihood of establishing a firm clinical diagnosis based on the appropriate PFA. This manuscript reviews the clinical presentation, chest imaging findings, duration and natural course of specific pleural effusions to help narrow the range of pre-thoracentesis diagnoses. A diagnosis of transudative effusion confirms an imbalance in hydrostatic and oncotic pressures, normal pleura and a limited differential diagnosis, which is typically apparent from the clinical presentation. Exudates are the result of infections, malignancies, inflammation, impaired lymphatic drainage or the effects of drugs, and pose a greater diagnostic challenge. The differential diagnosis for a pleural exudate can be narrowed if LDH levels exceed 1000 IU/L, the proportion of lymphocytes is ≥80%, pleural fluid pH is <7.30 or there is pleural eosinophilia of >10%.

Forced vital capacity in patients with idiopathic pulmonary fibrosis: test properties and minimal clinically important difference.

RATIONALE: Forced vital capacity (FVC) is an established measure of pulmonary function in idiopathic pulmonary fibrosis (IPF). Evidence regarding its measurement properties and minimal clinically important difference (MCID) in this population is limited. OBJECTIVES: To assess the reliability, validity, and responsiveness of FVC and estimate the MCID in patients with IPF. METHODS: The study population included all 1,156 randomized patients in two clinical trials of IFN-γ1b. FVC and other measures of functional status were measured at screening or baseline and 24-week intervals thereafter. Reliability was assessed based on two proximal measures of FVC, validity was assessed based on correlations between FVC and other measures of functional status, and responsiveness was assessed based on the relationship between 24-week changes in FVC and other measures of functional status. Distribution-based and anchor-based methods were used to estimate the MCID. MEASUREMENTS AND MAIN RESULTS: Correlation of percent-predicted FVC between measurements (mean interval, 18 d) was high (r = 0.93; P < 0.001). Correlations between FVC and other parameters were generally weak, with the strongest observed correlation between FVC and carbon monoxide diffusing capacity (r = 0.38; P < 0.001). Correlations between change in FVC and changes in other parameters were slightly stronger (range, r = 0.16-0.37; P < 0.001). Importantly, 1-year risk of death was more than twofold higher (P < 0.001) in patients with a 24-week decline in FVC between 5% and 10%. The estimated MCID was 2-6%. CONCLUSIONS: FVC is a reliable, valid, and responsive measure of clinical status in patients with IPF, and a decline of 2-6%, although small, represents a clinically important difference.